Respiratory distress syndrome (RDS) is an acute, severe pulmonary disorder that is the leading cause of morbidity and mortality in preterm infants. It is a major healthcare concern - costs associated with treatment of RDS and its complications exceed $2.4 billion annually in the US. Currently, animal-derived surfactants instilled intratracheally via an endotracheal tube (ETT) are standard of care for treating RDS, in conjunction with mechanical ventilation (MV). ETT intubation and MV are often associated with iatrogenic complications and may lead to bronchopulmonary dysplasia (BPD)/ chronic lung disease (CLD) in these infants. Thus, non-invasive ventilator strategies such as nasal continuous positive airway pressure (nCPAP) are being increasingly employed, but use of nCPAP precludes the use and benefits of early surfactant replacement therapy. Limited success has been achieved in delivering surfactants with currently available aerosol-generating devices. To overcome the critical barrier of effectively aerosolizing surfactant, Discovery Laboratories Inc. (Discovery Labs) is developing an aerosolization technology platform that is specifically designed to noninvasively deliver its proprietary KL4 peptide-containing synthetic surfactant (lucinactant). The objective of developing this "first-in-class" drug-device combination therapy is to obviate the need for ETT intubation to deliver surfactants to preterm infants with or at risk for RDS, and second, avoid the use of animal- derived products in this fragile population. Prototype and first generation aerosol devices and delivery systems have been developed, demonstrating technical feasibility of delivering aerosolized lucinactant;efficacy has also been demonstrated in a preterm animal model (lamb) of RDS. Discovery Labs is currently developing a second generation device, which it plans to take into the clinic. The objective of the Phase I proposal is to fully test this device and conduct characterization of the aerosolized drug product to ensure that it is optimized for delivery to preterm infants. Following completion of Phase I, Discovery Labs intends moving to the Phase II objective of conducting a pilot phase 2a, open-label, multicenter, dose escalation trial in preterm infants with or at risk for RDS. Although beyond the scope of this proposal, an expanded phase 2b study will be conducted, to be followed by a pivotal, Phase 3, which should support submission of an NDA for the dug-device combination product as a therapeutic strategy for prevention and treatment of RDS. PUBLIC HEALTH RELEVANCE: Respiratory distress syndrome (RDS), a severe lung disorder that is the most commonly seen complication in infants born prematurely is a significant health-care concern, costing in excess of $2.4 billion annually. RDS is currently treated with animal-derived surfactants that can only be administered via invasive endotracheal intubation of the infant airway, and mechanical ventilation, both of which have risks. Discovery Laboratories Inc. is developing a "first-in-class" drug-device combination therapy using a novel aerosol technology to noninvasively deliver its synthetic surfactant, and hence obviate the need for intubation to deliver surfactants to preterm infants with RDS, and at the same time, avoid the use of animal-derived products in this fragile population.